My research interests are in the area of mammalian gene regulation; in particular, we are interested in transcriptional regulation in the liver during development and disease. Liver-specific regulation of the mouse alpha-fetoprotein (AFP) gene is being investigated using a variety of biochemical and molecular genetic strategies in tissue culture cells and transgenic mice. In vitro studies allow us to characterize the interplay between transcription factors and AFP regulatory elements such as the AFP promoter and enhancers. AFP constructs are analyzed in liver cell lines to further explore the consequences of these interactions. Finally, to fully understand aspects of AFP regulation, we introduce AFP DNA constructs into the mouse germline to produce transgenic animals. Using the tools and resources of the human genome project, we recently cloned Zhx2 as a regulator of AFP expression. We are currently investigating the role of Zhx2 in the control of AFP as well as other hepatic genes. Interestingly, we have found that Zhx2 regulates liver genes that control serum lipid levels and can influence cardiovascular disease. We have generated a conditional null allele of Zhx2 and are using these mice to study the role of this factor in liver development, liver disease (including cancer) and cardiovascular disease.

We are also interested in how transcription factors are involved in the response to agents that cause liver damage and/or liver cancer. In particular, we are studying the response to peroxisome proliferators, phenobarbital, and PCBs. We are interested in the link between these chemicals, nutritional status, oxidative stress, transcription factors, epigenetic events, and liver cancer. These studies emphasize the use of transgenic and gene knock-out mice.